This is an application for a R15 that seeks to examine the relationship between a) the efficacy of cognitive behavioral therapy (CBT) and fluoxetine treatment in adolescents with a positive diagnosis for major depressive disorder (MDD), and b) brain structure and metabolic activity related to the processing of emotional information. We plan to recruit 45 adolescents (13-17 years old) and their parents through referrals. All adolescents and their parents will be interviewed along the following domains: (a) depressive symptoms and diagnosis, (b) stress symptoms, (c) patient and parent functional status, (d) measures of proposed mediational process in CBT, and (e) family history of depressive symptoms. Based on these interviews, adolescents will be assigned to three equally sized groups. Baseline information will be obtained from a group of adolescents with a negative diagnosis of MDD. Two other groups of adolescents with a positive diagnosis of MDD will be treated with either 12 weekly sessions of CBT or the administration of fluoxetine. Treatment will be provided by qualified licensed mental health professionals at either the Institute for Psychological Research at the University of Puerto Rico (UPR), R[unreadable]o Piedras Campus (CBT treatment group), or the Child and Adolescent Psychiatry Program at UPR, Medical Sciences Campus (SSRI treatment group). We plan to conduct evaluations at intake (week 0), mid-treatment (week 6), post-treatment (week 12), and follow-up (at 3 and 6 months post-treatment). All participants will also undergo brain imaging sessions at the functional magnetic resonance imaging (fMRI) facility at the San Jorge Children's Hospital to assess: a) brain activity associated to the processing of emotional content as measured by Blood Oxygen Level Dependent (BOLD) contrast (fMRI), b) BOLD-based resting-state functional connectivity among pre-selected brain regions of interest (fcMRI), c) microscopic white matter integrity as measured by fractional anisotropy brain maps generated with diffusion tensor imaging (DTI), and d) anatomical volume of selected brain regions (MRI). All participants will undergo scanning at intake. Participants with a positive diagnosis of MDD will also be scanned immediately after end of treatment and 6 months after end of treatment. One of the main goals of this research is to examine whether short and long-term treatment efficacy for each therapeutic modality is related to basal levels of brain activity and to any potential changes in post-treatment emotional content processing as measured by fMRI and fcMRI. The other goal is to measure whether treatment efficacy and performance in behavioral tasks involving emotional content are related to brain structure and structural connectivity between corticolimbic regions as measured by pre-treatment MRI and DTI scans. PUBLIC HEALTH RELEVANCE: The potential contribution of this study is that obtaining knowledge of the brain metabolic and structural characteristics of adolescents diagnosed with major depression, and how it relates to clinical measures, would allow personalized and more effective treatments for this population. This study will also provide scientific evidence on the efficacy of two of the most common modalities for treating major depression in adolescents: cognitive behavioral therapy and treatment with fluoxetine.